# Reactions of Plasmodium falciparum Type II NADH: Ubiquinone Oxidoreductase with Nonphysiological Quinoidal and Nitroaromatic Oxidants

## TL;DR

This study explores how a malaria parasite enzyme interacts with certain chemical compounds, revealing how they might kill the parasite.

## Contribution

The paper reveals distinct reduction mechanisms of quinones and nitroaromatics by PfNDH2 and proposes a new catalytic scheme.

## Key findings

- Quinones and nitroaromatics show reactivity trends based on their reduction potential and lipophilicity.
- Quinones and nitroaromatics bind to PfNDH2 at separate sites, supporting a ping-pong mechanism.
- Molecular docking shows lipophilic quinones have higher binding affinity to PfNDH2.

## Abstract

In order to detail the antiplasmodial effects of quinones (Q) and nitroaromatic compounds (ArNO2), we investigated their reduction mechanism by Plasmodium falciparum flavoenzyme type II NADH:ubiquinone oxidoreductase (PfNDH2). The reactivity of Q and ArNO2 (n = 29) follows a common trend and exhibits a parabolic dependence on their single-electron reduction potential (E71), albeit with significantly scattered data. The reactivity of quinones with similar E71 values increases with their lipophilicity. Quinones are reduced by PfNDH2 in a two-electron way, but ArNO2 are reduced in a single-electron way. The inhibition studies using NAD+ and ADP-ribose showed that quinones oxidize the complexes of reduced enzyme with NADH and NAD+. This suggests that, as in the case of other NDH2s, quinones and the nicotinamide ring of NAD(H) bind at separate sites. A scheme of PfNDH2 catalysis is proposed, consistent with both the observed ‘ping-pong’ mechanism and the presence of two substrate binding sites. Molecular docking showed that Q and ArNO2 bind in a similar manner and that lipophilic quinones have a higher affinity for the binding site. One may expect that PfNDH2 can be partially responsible for the previously observed enhanced antiplasmodial activity of aziridinylbenzoquinones caused by their two-electron reduction, as well as for the redox cycling and oxidative stress-type action of ArNO2.